ABSTRACT Type 2 diabetes is a highly heritable disease, yet only a small fraction of overall genetic risk has been explained. A new genetic marker associated with increased risk for type 2 diabetes has been found that accounts for a much greater risk than any gene identified to date. This genetic marker is in the TCF7L2 gene. Identification of how this genetic marker increases risk for type 2 diabetes could have a major impact on early diagnosis and prevention for the estimated 8% of the population that is homozygous for the risk allele and at high risk for this disease. The goal of this revised R21 application in response to PA-060155 Exploratory Grant Program in Diabetes Endocrinology and Metabolism is to determine the mechanism(s) through which a genetic marker in the TCF7L2 gene modifies individual risk for type 2 diabetes. New preliminary data from our lab suggests that the risk allele is not associated with a change in TCF7L2 expression but rather with altered localization of TCF7L2 in secretory cells. This coincides with new evidence that homozygosity for the risk allele is associated with increased expression of the secretory protein Chromogranin A. Interestingly, secretory neuroendocrine cells in the gut are absent in the TCF7L2 null mice, further suggesting a link between TCF7L2 and secretory cells. Endocrine and neuroendocrine cells in the gut and pancreas are unique in that they possess a regulated secretory system that allows for the fine tuning of glucose homeostasis. The TCF7L2 SNP rs7903146 most highly associated with risk of type 2 diabetes has also recently been associated with reduced insulin secretion in non-diabetic individuals, thereby providing more mechanistic insight that the defect is secretory in nature. In collaboration with the Broad Institute we will use a combination of novel approaches and resources including genotyped human tissue, the TCF7L2 null mouse model, and direct gain and loss of function experiments to test the hypothesis that the SNP most highly associated with risk of type 2 diabetes (rs7903146) is associated with a primary defect in the secretory cells in the colon and pancreas. If these findings are confirmed, this discovery could have significant impact on the estimated 8% of the population that is homozygous for the risk allele and at high risk for type 2 diabetes. We propose the following aims: [unreadable] [unreadable] I. Identify alterations in localization, expression, or splicing of TCF7L2 in the colon and pancreas associated with the SNP (rs7903146) that confers greatest risk for type 2 diabetes. [unreadable] [unreadable] II. Establish that homozygosity (TT) for the risk allele in TCF7L2 (rs7903146) is associated with a defect in the secretory cell population in the colon and pancreas.The number of people with diabetes in the world is projected to rise from 171 million to 366 million by year 2030. Type 2 diabetes is a highly heritable disease, yet only a small fraction of overall genetic risk of the disease has been explained. However, a recent discovery identified mutations in the gene, TCF7L2, that account for a much greater risk of developing type 2 diabetes. The purpose of this R21 application for Program Announcement (Exploratory Grant Program in Diabetes and Endocrinology and Metabolism) is to translate how a mutation in the TCF7L2 gene alters biological function and increases risk for type 2 diabetes. The long term goal is to understand basic mechanisms leading to type 2 diabetes and use this information to improve health care. [unreadable] [unreadable] [unreadable]